Allergic responses include what is referred to as allergic conjunctiva, which is basically a hypersensitivity reaction, which may occur as a component of hayfever or an independent ocular allergy. For example, allergic responses to ragweed, pollen and animal hair may result in minor eye symptoms of itching and redness. The eye, particularly the conjunctiva, has a relatively large number of mast cells. When allergens are present, they can bind to the immunoglobulin on the surface of these mast cells and trigger the breakdown, or what is known as the degranulation, of the cell. On degranulation, mast cell components, including histamines, are released into the environment outside the mast cell. Through a variety of mechanisms, these components can be responsible for symptoms associated with allergic responses such as itching, redness, lid swelling, vasodilatation and chemosis (edema of the conjunctiva). The patient commonly complains of a burning of the eyes.
Antihistamines are compounds which are administered to prevent histamines, released from mast cells in response to the presence of allergens, from binding to, for example, nerves and smooth muscle cells of the conjunctival blood vessels causing redness, itching and swelling. Thus, topical antihistamines do not block the release of histamine, but rather inhibit the allergic reaction by competing with histamine for the histamine receptors on effector cells. Historically, the term antihistamine has been used to describe drugs that act as H.sub.1 -receptor antagonists.
Topical antihistamines are commonly formulated in combination with a vasoconstrictor to create a product that also helps to relieve ocular injection. Clinically available antihistamines that competitively antagonize histamine to some extent include ethanolamines, ethylenediamines, alkylamines, phenothiazines or piperidines. Antihistamine preparations commercially available for topical ophthalmic use include 0.3% pheniramine maleate (an alkylamine), 0.5% antazoline phosphate (an ethylenediamine), and 0.1% pyrilamine maleate (also an ethylenediamine). Conventional vasoconstrictors include, for example, ephedrine, naphazoline, phenylephrine, and tetrahydrozoline.
One commercially available product for treating allergic conjunctivitis, OPCON-A.RTM. eyedrops, is a sterile aqueous ophthalmic solution containing 0.025% naphazoline hydrochloride and 0.3% pheniramine maleate, further in combination with the inactives hydroxypropyl methylcellulose, sodium chloride, sodium borate, and edetate disodium, preserved with 0.01% benzalkonium chloride. Such products combine the effects of the antihistamine, pheniramine maleate, with the decongestant or vasoconstrictor naphazoline.
In addition to antihistamines used to treat allergic symptoms, a variety of demulcents are known for topical administration to the eye to protect and lubricate mucous membrane surfaces and relieve dryness and irritation. Conventional demulcents include carboxymethyl cellulose, hydroxyethyl cellulose and other cellulose derivatives, dextran, gelatin, and polyols such as glycerin, polyethylene glycol, polysorbate, propylene glycol, polyvinyl alcohol, and povidone. For example, U.S. Pat. No. 4,120,949 discloses the use of polyvinylpryrrolidone (also referred to as povidone or PVP) as a demulcent. Rankin, in U.S. Pat. No. 3,920,810, discloses the use of polyvinylpyrrolidone (PVP) as a demulcent and lubricant in solutions used to treat dry eye. PVP is known to act as a demulcent lubricant by means of a combination of adhesive and lubricating properties that aid in the spreading of its viscous solution.
A problem with products on the market for treating allergic conjunctivitis is that, despite the use of such products, patients continue to complain about burning and itching. Thus, a more effective product or a product treating a greater range of symptoms is desirable. Furthermore, it would be desirable to provide a single composition that would effectively respond to a fuller range of symptoms, including dryness, itching, and burning. It has been found that, contrary to intuition (because allergic responses may include watering of the eyes), dryness is often associated with allergic conditions, and that compositions that alleviate the symptoms of dryness more fully respond to the range of symptoms associated with the allergic responses. It would, therefore, be desirable to be able to effectively and simultaneously treat both dryness and allergic reactions by the administration of a single composition. Finally, it would be desirable if such compositions could be administered to patients irrespective of whether they were wearing contact lenses.
It is, therefore, an object of the present invention to provide improved ophthalmic compositions comprising an antihistamine for treating allergic responses, including redness and itching, that is comfortable and that elicits minimal stinging. It is a further object to provide an ophthalmic composition designed to alleviate dryness. Finally, it is an object to provide methods for treating ophthalmic allergic conditions through administration of the disclosed compositions.